A Phase 3 interventional study of autologous EBV specific Cytotoxic T cells and combination IV gemcitabine and IV carboplatin (AUC2) in Nasopharyngeal Carcinoma, sponsored by Tessa Therapeutics. Completed at 30 sites in 5 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-06-28.
Sponsored by Tessa Therapeutics · Phase 3, Interventional, and Treatment
This study is a multi-center, randomized, open label, Phase III clinical trial for advanced Nasopharyngeal Carcinoma(NPC) Patients.
Drugs used in chemotherapy, such as gemcitabine and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving an infusion of a person's cytotoxic T cells (CTL) that have been treated in the laboratory may help the body build an effective immune response to kill tumor cells. Giving combination chemotherapy together with laboratory-treated T cells may kill more tumor cells. This Phase III trial is to assess if combined gemcitabine-carboplatin (GC) followed by adoptive T-cell therapy would improve clinical outcome for patients with advanced nasopharyngeal carcinoma (NPC). It is also the world's first, and largest, Phase 3 T-cell therapy cancer trial ever conducted, and enrollment is ongoing for 330 patients from 30 hospital centers across Asia and the United States.
This clinical trial is conducted on the back of a successful Phase 2 NPC trial involving 38 patients at the National Cancer Centre, Singapore. This trial produced the best published 2-year (62.9%), and median overall survival (OS) data (29.9 months) in 35 patients with advanced NPC who received autologous EBV-specific CTL. Kindly see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978790/ for the Phase 2 publication titled "Adoptive T-cell Transfer and Chemotherapy in the First line treatment of Metastatic and/or Locally Recurrent Nasopharyngeal Carcinoma".
330 patients will be randomized after their eligibility status has been fully determined and informed consent has been obtained. Patients will be randomly allocated to receive either Arm A (Gemcitabine and Carboplatin (GC) x 4* cycles and EBV-specific CTL) or Arm B (GC x 6 cycles alone) in a 1:1 ratio using a stratified block randomization scheme. The stratification variables are country and disease stage (metastatic vs locally recurrent). *Additional 1-2 chemotherapy cycles (up to total 6 chemo cycles) might be given upon discretion of Investigator, if EBV-specific CTL infusions are not available in time for the 1st scheduled infusion.
After randomization, patients in Arm A will have their peripheral blood taken for the establishment of cytotoxic T cell line and EBV transformed lymphoblastoid cell line (CTL). Within two weeks of enrollment, patients will commence combination GC chemotherapy for a total of 4 cycles. Patients in Stage 2 of study will receive the EBV-specific CTL immunotherapy.
As of 1 May 2020, patients who have not received the first infusion of EBV-specific CTLs, will instead continue to receive a total of 6 cycles combination of Gemcitabine (1000 mg/m2) and carboplatin (AUC2) on Days 1, 8, 15 every 28 days
6,741 studies on the registry are indexed under Carcinoma; 1,161 are open to participants now.
This study's enrollment of 330 is above the median of 45 across 5,170 interventional studies indexed under Carcinoma.
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Key Inclusion Criteria
Metastatic or locally recurrent EBV-positive, non-keratinizing and/ or undifferentiated NPC* who do not have curative options such as chemo-radiation or surgery
*Subjects will be enrolled based on confirmed histology diagnosis of the NPC
Human Immunodeficiency Virus (HIV) negative*
* Status of HIV must be confirmed via a HIV antibody test or other confirmatory tests available within 4 weeks of screening
Key Exclusion Criteria
HIV Positive*
* Status of HIV must be confirmed via a HIV antibody test or other confirmatory tests available within 4 weeks of screening
Prior anti-cancer treatment for metastatic or locally recurrent disease, EXCEPT:
For metastatic or locally recurrent disease, localised palliative radiotherapy is allowed.
For locally recurrent disease, the following treatment is allowed
The following is allowable:
4 cycles\* of combination IV Gemcitabine (1000 mg/m2) and IV carboplatin (AUC2) on Days 1, 8, 15 every 28 days, followed sequentially by T-cell immunotherapy (2 cycles) of autologous EBV specific Cytotoxic T cells every 2 weeks, followed by EBV-specific CTL immunotherapy (4 cycles) every 8 weeks after 6 weeks from the second cycle. \*Additional 1-2 chemotherapy cycles (up to total 6 chemo cycles) might be given upon discretion of Investigator, if EBV-specific CTL infusions are not available in time for the 1st scheduled infusion. As of 1 May 2020, patients who have not received the first infusion of EBV-specific CTLs, will instead continue to receive a total of 6 cycles combination of Gemcitabine (1000 mg/m2) and carboplatin (AUC2) on Days 1, 8, 15 every 28 days
Biological: autologous EBV specific Cytotoxic T cells · Drug: combination IV gemcitabine and IV carboplatin (AUC2)
6 cycles of combination IV gemcitabine (1000 mg/m2) and IV carboplatin (AUC2) on Days 1, 8, 15 every 28 days.
Drug: combination IV gemcitabine and IV carboplatin (AUC2)
The CTL line will be prepared by co-cultivation of the irradiated EBV-LCL with patient PBMC. A proportion of peripheral blood will be used to generate EBV specific CTLs.
4 cycles for Arm A and 6 cycles for Arm B
Overall Survival (OS) of Subjects With Advanced Nasopharyngeal Carcinoma.
Efficacy of EBV-CTL following first line chemotherapy was compared to chemotherapy alone in terms of OS of subjects with advanced nasopharyngeal carcinoma. Overall survival was defined as the duration in months from the day of randomization until death from any cause for a subject known to be deceased, or censored at the last contact date that a subject was known to be alive or lost to follow-up.
Time frame: From randomization until death, assessed up to 7 years. Survivors and lost to follow-up subjects were censored at the date of last contact. Survival follow-up was done every 12 weeks from end of treatment.
Progression-free Survival (PFS) of Subjects With Advanced Nasopharyngeal Carcinoma.
Progression-free survival was defined as the duration from randomization to the first occurrence of documented disease progression \[based on imaging results\] or death from any cause, whichever occurred first.
Time frame: From randomization until first occurrence of disease progression or death of any cause, whichever occurred first, assessed up to 7 years. Subjects who received subsequent anti-cancer therapy were censored at the date of last tumor assessment.
Overall Response Rate (ORR) of Subjects With Advanced Nasopharyngeal Carcinoma.
Overall response rate was assessed by sites using computed tomography/magnetic resonance imaging based on RECIST version 1.1, which defined Complete Response (CR) as disappearance of all lesions and pathologic lymph nodes; Partial Response (PR) as \>=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; Stable disease (SD) as no PR and no progressive disease (PD); PD as \>=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. The ORR for each treatment arm was comprised of the proportion of subjects who achieved a best overall response of CR or PR while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline. Subjects who achieved CR or PR are responders, otherwise are non-responders.
Time frame: From randomization until End of Treatment, an average of 13 months for the gemcitabine+carboplatin and EBVCTL arm and 6 months for the gemcitabine+carboplatin only arm.
Clinical Benefit Rate (CBR) of Subjects With Advanced Nasopharyngeal Carcinoma.
Clinical benefit rate (CBR) was assessed using computed tomography/magnetic resonance imaging based on RECIST version 1.1., which defined CR as disappearance of all lesions and pathologic lymph nodes; PR as \>=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; SD as no PR and no PD; PD as \>=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. CBR was defined as the proportion of subjects who achieved CR, PR, or SD while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline.
Time frame: From randomization until End of Treatment, an average of 13 months for the gemcitabine+carboplatin and EBVCTL arm and 6 months for the gemcitabine+carboplatin only arm.
Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma.
Best overall response (BOR) was assessed using computed tomography/magnetic resonance imaging based on RECIST version 1.1., which defined CR as disappearance of all lesions and pathologic lymph nodes; PR as \>=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; SD as no PR and no PD; PD as \>=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. The BOR of each treatment arm consisted of CR, PR, SD, PD, NE, and NA while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline. The ORR was comprised of the proportion of subjects who achieved a BOR of CR or PR.
Time frame: From randomization until End of Treatment, an average of 13 months for the gemcitabine+carboplatin and EBVCTL arm and 6 months for the gemcitabine+carboplatin only arm.
This study randomized 330 subjects at 23 sites in Asia and 7 sites in the United States from 17 Jul 2014 to 28 Feb 2022.
| Milestone | Chemo + EBV-CTL | Chemo Only |
|---|---|---|
| Started | 164 | 166 |
| Treatment received: gemcitabine/ carboplatin | 163 | 162 |
| Treatment received: ebv-ctl | 133 | 0 |
| Completed | 55 | 99 |
| Not completed | 109 | 67 |
| Withdrew: Adverse event | 5 | 15 |
| Withdrew: Death | 16 | 8 |
| Withdrew: Lost to follow-up | 0 | 1 |
| Withdrew: Withdrawal by subject | 14 | 7 |
| Withdrew: Progressive disease | 69 | 21 |
| Withdrew: No study drug | 2 | 0 |
| Withdrew: Randomized by mistake with study treatment | 0 | 1 |
| Withdrew: Non-compliance with study schedule | 1 | 0 |
| Withdrew: Other | 1 | 10 |
| Withdrew: Not treated | 1 | 4 |
Efficacy of EBV-CTL following first line chemotherapy was compared to chemotherapy alone in terms of OS of subjects with advanced nasopharyngeal carcinoma. Overall survival was defined as the duration in months from the day of randomization until death from any cause for a subject known to be deceased, or censored at the last contact date that a subject was known to be alive or lost to follow-up.
| Months | Chemo + EBV-CTL | Chemo Only |
|---|---|---|
| Overall Survival (OS) of Subjects With Advanced Nasopharyngeal Carcinoma. | 25 (19.7 to 31.8) | 24.9 (19.7 to 32.8) |
Progression-free survival was defined as the duration from randomization to the first occurrence of documented disease progression \[based on imaging results\] or death from any cause, whichever occurred first.
| Months | Chemo + EBV-CTL | Chemo Only |
|---|---|---|
| Progression-free Survival (PFS) of Subjects With Advanced Nasopharyngeal Carcinoma. | 7.9 (7.1 to 8.2) | 8.5 (8.1 to 9.6) |
Overall response rate was assessed by sites using computed tomography/magnetic resonance imaging based on RECIST version 1.1, which defined Complete Response (CR) as disappearance of all lesions and pathologic lymph nodes; Partial Response (PR) as \>=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; Stable disease (SD) as no PR and no progressive disease (PD); PD as \>=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. The ORR for each treatment arm was comprised of the proportion of subjects who achieved a best overall response of CR or PR while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline. Subjects who achieved CR or PR are responders, otherwise are non-responders.
| Participants | Chemo + EBV-CTL | Chemo Only |
|---|---|---|
| Responders (CR/PR) | 100 | 105 |
| Non-Responders (SD/PD/NA/NE) | 64 | 61 |
Clinical benefit rate (CBR) was assessed using computed tomography/magnetic resonance imaging based on RECIST version 1.1., which defined CR as disappearance of all lesions and pathologic lymph nodes; PR as \>=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; SD as no PR and no PD; PD as \>=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. CBR was defined as the proportion of subjects who achieved CR, PR, or SD while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline.
| Participants | Chemo + EBV-CTL | Chemo Only |
|---|---|---|
| Clinical Benefit (CR/PR/2 consecutive SD) | 139 | 136 |
| No Clinical Benefit (Otherwise) | 25 | 30 |
Best overall response (BOR) was assessed using computed tomography/magnetic resonance imaging based on RECIST version 1.1., which defined CR as disappearance of all lesions and pathologic lymph nodes; PR as \>=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; SD as no PR and no PD; PD as \>=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. The BOR of each treatment arm consisted of CR, PR, SD, PD, NE, and NA while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline. The ORR was comprised of the proportion of subjects who achieved a BOR of CR or PR.
| Participants | Chemo + EBV-CTL | Chemo Only |
|---|---|---|
| Complete Response (CR) | 6 | 14 |
| Partial Response (PR) | 94 | 91 |
| Stable Disease (SD) | 45 | 41 |
| Progressive Disease (PD) | 9 | 10 |
| NE (Not evaluable) | 1 | 0 |
| NA (Not applicable) | 9 | 10 |
Collected over Adverse events during the entire trial duration were monitored/assessed from randomization to end of treatment (approximately 13 months for Chemo+EBV-CTL and 6 months for Chemo Only).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Chemo + EBV-CTL | 16/163 (9.8%) | 68/163 (41.7%) | 163/163 (100%) |
| Chemo Only | 8/162 (4.9%) | 46/162 (28.4%) | 162/162 (100%) |
| Event | Chemo + EBV-CTL | Chemo Only |
|---|---|---|
| HyponatremiaMetabolism and nutrition disorders | 10/163 | 2/162 |
| PneumoniaInfections and infestations | 9/163 | 8/162 |
| AnemiaBlood and lymphatic system disorders | 9/163 | 6/162 |
| Nasopharyngeal cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 9/163 | 6/162 |
| PyrexiaGeneral disorders | 7/163 | 4/162 |
| febrile neutropeniaBlood and lymphatic system disorders | 5/163 | 4/162 |
| SepsisInfections and infestations | 0/163 | 3/162 |
| Septic shockInfections and infestations | 3/163 | 1/162 |
| Cerebrovascular accidentNervous system disorders | 3/163 | 0/162 |
| SeizureNervous system disorders | 3/163 | 0/162 |
| Event | Chemo + EBV-CTL | Chemo Only |
|---|---|---|
| AnemiaBlood and lymphatic system disorders | 111/163 | 101/162 |
| Platelet count decreasedInvestigations | 61/163 | 81/162 |
| Neutrophil count decreasedInvestigations | 59/163 | 66/162 |
| NeutropeniaBlood and lymphatic system disorders | 63/163 | 65/162 |
| White blood cell count decreasedInvestigations | 60/163 | 59/162 |
| ThrombocytopeniaBlood and lymphatic system disorders | 47/163 | 52/162 |
| LeukopeniaBlood and lymphatic system disorders | 39/163 | 49/162 |
| ConstipationGastrointestinal disorders | 48/163 | 45/162 |
| PyrexiaGeneral disorders | 43/163 | 27/162 |
| FatigueGeneral disorders | 36/163 | 38/162 |
Intent-to-treat Analysis Set - all subjects randomized to treatment.
| Age, Continuous(years) | Chemo + EBV-CTL | Chemo Only | Total |
|---|---|---|---|
| Median | 53 (30 to 80) | 55 (21 to 79) | 54 (21 to 80) |
| Sex: Female, Male(Participants) | Chemo + EBV-CTL | Chemo Only | Total |
|---|---|---|---|
| Female | 42 | 40 | 82 |
| Male | 122 | 126 | 248 |
| Ethnicity (NIH/OMB)(Participants) | Chemo + EBV-CTL | Chemo Only | Total |
|---|---|---|---|
| Hispanic or Latino | 1 | 0 | 1 |
| Not Hispanic or Latino | 156 | 157 | 313 |
| Unknown or Not Reported | 7 | 9 | 16 |
| Race (NIH/OMB)(Participants) | Chemo + EBV-CTL | Chemo Only | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 160 | 160 | 320 |
| Native Hawaiian or Other Pacific Islander | 1 | 0 | 1 |
| Black or African American | 0 | 1 | 1 |
| White | 2 | 5 | 7 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 1 | 0 | 1 |
| Region of Enrollment(Participants) | Chemo + EBV-CTL | Chemo Only | Total |
|---|---|---|---|
| Singapore | 17 | 17 | 34 |
| United States | 14 | 15 | 29 |
| Taiwan | 34 | 34 | 68 |
| Malaysia | 53 | 53 | 106 |
| Thailand | 46 | 47 | 93 |
| Nasopharyngeal Cancer (NPC) stage at time of study entry(Participants) | Chemo + EBV-CTL | Chemo Only | Total |
|---|---|---|---|
| Stage II | 15 | 5 | 20 |
| Stage III | 15 | 16 | 31 |
| Stage IVA | 14 | 24 | 38 |
| Stage IVB | 23 | 34 | 57 |
| Stage IVC | 94 | 84 | 178 |
| Others | 3 | 3 | 6 |
| Disease Status per Randomization Stratification(Participants) | Chemo + EBV-CTL | Chemo Only | Total |
|---|---|---|---|
| Metastatic | 115 | 116 | 231 |
| Locally recurrent | 49 | 50 | 99 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)(Participants) | Chemo + EBV-CTL | Chemo Only | Total |
|---|---|---|---|
| ECOG PS 0 | 87 | 99 | 186 |
| ECOG PS 1 | 73 | 65 | 138 |
| ECOG PS 2 | 4 | 2 | 6 |
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